PROPOSAL SUMMARY/ABSTRACT Colorectal cancer (CRC) is third most commonly diagnosed and second most deadly cancer in the United States. Several risk factors, including genetic predispositions and chronic inflammation from inflammatory bowel disease, have been identified as risk factors for CRC development. Recently, obesity has been identified as a major risk factor for CRC development. More than one third of the entire population of the United States is clinically obese. Thus, because of the sheer magnitude of the population at risk for CRC, further studies investigating the mechanisms by which obesity modulates risk are required. NOD-like receptors (NLRs), a class of innate immune receptors are important mediators that both activate and inhibit inflammatory responses. Our laboratory focuses on the study of the inhibitory NLRs (iNLR), a subclass of NLRs, which potently inhibit pro- inflammatory signaling and cytokine production. iNLR deficiency exacerbates experimental colitis and colitis- associated colorectal cancer. Recently, our laboratory also identified a microbiota-dependent role for iNLR in the regulation of colitis and both sporadic and colitis-associated colon cancer. Thus, iNLR represents a host factor that potentially links the chronic inflammation and microbial dysbiosis that define obesity, leading to obesity- associated colorectal cancer (O-CRC). I hypothesize that inhibition of inflammation by iNLR is necessary to promote a beneficial microbial milieu in the gut in order to mitigate O-CRC risk. Firstly, I will characterize the role of iNLR in O-CRC (Aim 1). Our laboratory has generated myeloid-specific and epithelial-specific iNLR deficient mice for use in determining the cells in which iNLR exerts the largest effect on O-CRC. I will employ several murine O-CRC models to investigate tumorigenesis, dysplasia, cytokine and adipokine production, inflammatory cell infiltration, and pro-inflammatory signaling. I will also examine changes in the microbiota and the downstream effects of such changes on disease onset and progression (Aim 2). Finally, I will establish clinical relevance by assessing the impact of iNLRs, cytokine mRNA levels and the microbiome of healthy and obese individuals in O-CRC risk (Aim 3). Together, these data will reveal critical links between iNLR, inflammation, and the microbiome during O-CRC. In sum, this proposal aims to characterize the role of iNLR in O-CRC and the extent to which the interplay between the innate immune system and the gut microbiome alters O-CRC in mice and humans. The data generated by the studies in this application may potentially reveal novel biomarkers for or avenues for therapeutic intervention in O-CRC.